Despite the success of highly active antiretroviral therapy (HAART) in reducing plasma virus levels to below the limit of detecfion, eradication of the infection has not been achieved due to the persistence of virus in stable reservoirs. A major problem in the analysis of such strategies is the rapidly changing therapeutic landscape. Improved HAART regimens offer patients the prospect of complete control of viral replication with minimal toxicity. In this situation, it is more difficult to test experimental attempts to purge viral reservoirs if there is the possibility of negative consequences for the patient. Progress towards curing HIV-1 infection will therefore be critically dependent upon a reliable animal model in which eradication strategies can be realistically evaluated. We have previously shown that a latent viral reservoir in resting CD4+ T cells is established in SIV infected macaques. The collaborative studies carried out in the initial funding period have led to the development of an SIV/macaque model in which viremia can be controlled by HAART. In the proposed studies, we will establish that the degree of suppression of viral replication and the nature of the residual viremia'that confinues despite HAART are similar to what is observed in humans on HAART. In collaboration with other PPG investigators, we will explore other potential reservoirs, including those that cannot be readily studied in humans. In preliminary studies, we have developed a novel primary cell assay for HIV-1 latency, and we are using this assay to identify compounds that activate latent HlV-1 without inducing global T cell activation. Several promising hits have been identified, all distinct from previously described activators. The toxicity profiles of some of these compounds may allow them to be tested for ability to reduce the size of the latent reservoir in SIV-infected macaques on HAART. Together, these preliminary studies put us in a unique position to explore the feasibility of HlV-1 eradication in a realistic animal model.